Recent developments in anti-angiogenic and vascular-disrupting therapies as well as hypofractionated radiotherapy have shown the great potential of tumor vasculature as a therapeutic target for cancer medicine. We have an original idea for using targeted gold nanoparticles as vascular disruptive agents (VDA) in conjunction with clinical megavoltage photon beams. Unlike competing proposals, we recognize that gold nanoparticles tend to accumulate in, and can even be targeted for, tumor blood vessels and that these structures may be more important for anti-cancer therapy than clonogenic cell death. Due to the short distance traveled by x-ray induced photoelectrons, the endothelial cells of the tumor will receive a sizable boost in dose, even for clinical megavoltage photon irradiation. We are proposing a therapy that would be highly compatible with current clinical practice and could offer a substantial clinical benefit. Upon the successful completion of the aims, we will have demonstrated the validity of two underlying premises: 1) gold nanoparticles can be effectively, and safely, targeted to the tumor endothelium, and 2) the incidence of endothelial cell apoptosis during radiotherapy will be highly correlated to the proximity and local concentrations of gold nanoparticles. PUBLIC HEALTH RELEVANCE: The goal of this project is the improvement of cancer therapy by employing gold nanoparticles, specifically targeted to tumor blood vessels, during radiation therapy. These nanoparticles will give off an extra radiation dose to their immediate surroundings during therapeutic irradiation. The ensuing collapse of the tumor vasculature could lead to large scale cancer cell death and potentially halt metastasis.